NM_015114.3:c.2616-144G>A

Variant names:

• chr12-132727587-C-T
• rs10437914
• NM_015114.3:c.2616-144G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015114.3(ANKLE2):​c.2616-144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (20 hom., cov: 0)
  • Exomes 𝑓: 0.22 (6856 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKLE2 NM_015114.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.196
• Publications: 1 publications found

Genes affected

ANKLE2 (HGNC:29101): (ankyrin repeat and LEM domain containing 2) This gene encodes a member of the LEM family of inner nuclear membrane proteins. The encoded protein functions as a mitotic regulator through postmitotic formation of the nuclear envelope. Mutations in this gene cause morphology defects in the nuclear envelope and BAF hyperphosphorylation. [provided by RefSeq, Mar 2014]

ANKLE2 Gene-Disease associations (from GenCC):

• microcephaly 16, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-132727587-C-T is Benign according to our data. Variant chr12-132727587-C-T is described in ClinVar as Benign. ClinVar VariationId is 1240707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015114.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE2	NM_015114.3	MANE Select	c.2616-144G>A		intron	N/A	NP_055929.1	Q86XL3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE2	ENST00000357997.10	TSL:1 MANE Select	c.2616-144G>A		intron	N/A	ENSP00000350686.5	Q86XL3-1
	ANKLE2	ENST00000542282.5	TSL:1	c.681-144G>A		intron	N/A	ENSP00000437807.1	Q86XL3-3
	ANKLE2	ENST00000539605.5	TSL:1	n.9115-144G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.181 AC: 11177 AN: 61784 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.167

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.191

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.219 AC: 85968 AN: 391876 Hom.: 6856 AF XY: 0.219 AC XY: 44783 AN XY: 204306

African (AFR) AF: 0.192 AC: 1998 AN: 10406

American (AMR) AF: 0.369 AC: 4788 AN: 12976

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 1827 AN: 9028

East Asian (EAS) AF: 0.346 AC: 3309 AN: 9556

South Asian (SAS) AF: 0.173 AC: 6058 AN: 34986

European-Finnish (FIN) AF: 0.290 AC: 4162 AN: 14374

Middle Eastern (MID) AF: 0.291 AC: 601 AN: 2062

European-Non Finnish (NFE) AF: 0.212 AC: 59348 AN: 279346

Other (OTH) AF: 0.203 AC: 3877 AN: 19142

GnomAD4 genome AF: 0.181 AC: 11185 AN: 61858 Hom.: 20 Cov.: 0 AF XY: 0.192 AC XY: 5744 AN XY: 29888

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.165 AC: 2974 AN: 18006

American (AMR) AF: 0.181 AC: 1038 AN: 5748

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 204 AN: 1262

East Asian (EAS) AF: 0.200 AC: 340 AN: 1700

South Asian (SAS) AF: 0.206 AC: 456 AN: 2212

European-Finnish (FIN) AF: 0.262 AC: 950 AN: 3620

Middle Eastern (MID) AF: 0.170 AC: 19 AN: 112

European-Non Finnish (NFE) AF: 0.177 AC: 4965 AN: 28008

Other (OTH) AF: 0.186 AC: 151 AN: 810

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.360 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.50
DANN	Benign	0.76
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10437914; hg19: chr12-133304173; COSMIC: COSV63294610; COSMIC: COSV63294610;